This study will define mucosal virulence and mechanism of innate immune host defense against aerosolized Rift Valley fever virus, a Category A biodefense pathogen. Rift Valley Fever virus (RVFV) is designated a priority pathogen based upon its projected severe impact on public health and agriculture in North America in the event of a deliberate release. Transmission to humans can occur either by mosquito bite, food contamination or aerosol inhalation during exposure to body fluids of RVFV-infected livestock. Whether the transmission route determines the severity of human RVF is not well defined, nor is it known which route is of primary importance during epizootics. Human RVF disease manifests most commonly as an acute self-limiting febrile illness, but can also lead to encephalitis, retinitis, and hemorrhagic fever. When hemorrhagic disease occurs, it usually begins on day 3 of illness;this acute onset of severe disease suggests an important role for innate immunity in defining human RVF disease manifestations. The mechanisms of aerosolized RVFV infection and mucosal immunity that are critical for protective immunity are poorly understood. In human infection, a delayed onset of type I IFN production is associated with the more severe forms of RVFV-induced clinical disease. Members of the Toll-like receptor (TLRs) and RNA helicase families are germ-line encoded pattern-recognition receptors (PRRs) capable of detecting viral pathogen associated molecular patterns (PAMPs). When activated, PRRs stimulate type I IFN and other inflammatory cytokine responses to control viral replication and disease. We propose to define RVFV virulence and innate immune responses in different mucosal cell types hypothesized to be critical for host defense against aerosolized RVFV. Therefore, we will develop in vitro human and murine models of aerosolized RVFV infection to define the role of innate PRRs in mucosal responses and clinical disease pathogenesis. We hypothesize that type I IFN responses to RVFV infection in the oral and pulmonary mucosa is directed by innate PRRs of infected epithelial cells and localized immune cells, and that the intensity and duration of this response is dependent on viral dose, mucosal cell permissiveness and immune cell migration. Specifically, we aim to define innate immunity to RVFV infection in human mucosa and to define the role of nonstructural RVFV proteins NSs and NSm in infection and the innate immune response utilizing a murine model of aerosolized attenuated RVFV infection. We proposed highly relevant studies to define the innate immune receptors and pathways involved in early host defense against Rift Valley fever Virus. Rift Valley Fever virus (RVFV), a Phlebovirus in the Bunyaviridae family, is designated a Category A biodefense pathogen based upon its projected severe impact on public health and agriculture in North America in the event of a deliberate release. Transmission to humans can occur either by mosquito bite, food contamination or aerosol inhalation. Human RVF disease manifests most commonly as an acute self-limiting febrile illness, but can also lead to encephalitis, retinitis, and hemorrhagic fever. Our studies to define mucosal innate immune responses to RVFV are novel, relevant and have potential to expand prevention and treatment options. Additionally, the research tools that we develop, including a murine inhalation model will have wider applicability to the study of viruses transmitted via a respiratory route.